Prostate cancer is the leading cancer among U.S. men. The biggest limitation of current prostate cancer management is that currently it is essentially impossible to accurately prognosticate which patients harbor aggressive cancers that progress into a metastatic disease and need treatment and which patients have non- aggressive indolent cancers that would not pose harm. Currently available techniques to progrnosticate prostate cancer suffer from lack of clinical utility, high cost and/or lack of sensitivity. We propse a new paradigm to accurately identify patients harboring aggressive versus non-aggressive disease among men with prostate cancer managed with active surveillance (repeat biopsies every 1-3 years). We propose to achieve this by detecting prostate field carcinogenesis, which is the notion that the genetic or environmental milieu that results in carcinogenesis impacts upon the entire prostate. Hence, not only tumor cells but also a much larger population of cells throughout the prostate which otherwise would appear normal on a biopsy - bear the fingerprint of the risk of aggressive cancer. Some of the first alterations that develop in cells in field carcinogenesis are at the nanoscale level and are too small to be detected by conventional microscopy, as with a pathologist examining prostate biopsies. We have developed a new optical technology, Partial Wave Spectroscopic (PWS) microscopy (or simply, nanocytology), which is uniquely suited to detect these subtle alterations in field carcinogenesis. We have validated nanocytology in prior clinical trials in seven types of cancer (lung, colon, prostate, ovarian, esophageal, pancreatic, and thyroid) in 759 patients. In a recent study of prostate cancer patients with Gleason 6 disease undergoing Active Surveillance (n = 38), we found that PWS nanocytology performed on histologically normal prostate epithelium was able to successfully predict subsequent progressors versus non-progressors. In the future, we envision that nanocytology can be coupled into existing prostate cancer care. The patients with prostate cancer who already undergo active surveillance will have their biopsies examined via PWS nanocytology, which will identify patients with aggressive versus non-aggressive tumors. In order to achieve this goal, as part of this SBIR Fast-track application NanoCytomics will first develop a fully-automated, whole-slide, fast PWS nanocytology system that is specifically optimized to acquire data on prostate cancer histological sections (Phase I). In Phase II, NanoCytomics will develop standard operating procedures and will develop improved biomarkers that can more accurately identify clinically significant prostate cancer. In Phase II, we will also validate the biomarkers on an independent data set by performing PWS on archival index biopsies in men diagnosed with prostate cancer who have had a prostatectomy after 3 to 10 years of clinical follow-up after the index biopsy. Our goal is that by the time the project is completed the technology will be fully developed, clinically tested and ready for FDA trials and clinical use.